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Find out more about navigating Wikipedia and finding information.

This article is about the

drug. For the musical about

a person with

Thalidomide disability,

see Thalidomide!! A Musical .

Thalidomide was sold in a number of countries across the world from 1957 until 1961 when it was withdrawn

from the market after being found to be cause birth defects in what has been called "the biggest medical

tragedy of modern times".[3]

It is not known exactly how many worldwide victims of the drug there have been,

although estimates range from 10,000 to 20,000.[4]

Since then thalidomide has been found to be a valuable treatment for a number of medical conditions and it is

being prescribed again in a number of countries, although its use remains controversial.[5][6]

The thalidomide

tragedy led to much stricter testing being required for drugs and pesticides before they can be licensed.[7]

Thalidomide (pronounced /θəˈlɪdəmaɪd/) is a sedative-hypnotic and multiple myeloma medication. The drug is

a potent teratogen in rabbits and primates including humans: severe birth defects may result if the drug is taken

during pregnancy.[2]

Article Discussion Edit this page History

258.23 g/mol

?

55% and 66% for the (+)-R and (–)-S

enantiomers, respectively

Hepatic (CYP2C19)[1]

Thalidomide

Systematic (IUPAC) name

2-(2,6-dioxopiperidin-3-yl)-1H -isoindole-1,3(2H )-dione

Identifiers

CAS number 50-35-1

ATC code L04AX02

PubChem 5426

DrugBank APRD01251

ChemSpider 5233

Chemical data

Formula C13H10N2O4

Mol. mass

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability

Protein binding

Metabolism

Contents [hide]

● 1 History

● 2 Possible indications

● 3 Teratogenic mechanism

● 4 Other side effects

● 5 Thalidomide analogs

�❍ 1.1 Development

�❍ 1.2 Birth defects

�❍ 1.3 Revived interest

�❍ 1.4 United States

�❍ 1.5 United Kingdom

�❍ 1.6 Brazil

�❍ 2.1 Thalidomide and multiple myeloma

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Thalidomide was said to have been developed by German pharmaceutical company Grünenthal in Stolberg

(Rhineland) near Aachen, although this claim has recently been challenged. A report published by Dr Martin W

Johnson, director of the Thalidomide Trust in the UK, detailed evidence that suggested the drug had been

developed under the direction of a Nazi scientist in 1944, as an antidote to nerve gases such as sarin, ten

years before Grünenthal secured a patent in 1954.[8]

Thalidomide was found to act as an effective tranquiliser

and painkiller and was proclaimed as a "wonder drug" for insomnia, coughs, colds and headaches. It was also

found to be an effective antiemetic which had an inhibitory effect on morning sickness, and so thousands of

pregnant women took the drug to relieve their symptoms.[4]

At the time of the drug's development it was not

thought likely that any drug could pass from the mother across the placental barrier and harm the

developing foetus.[7]

In the late 50s and early 60s, more than 10,000 children in 46 countries

were born with deformities such as phocomelia, as a consequence

of thalidomide use.[9]

The Australian obstetrician William McBride and

the German pediatrician Widukind Lenz suspected a link between birth

defects and the drug, and this was proved by Lenz in 1961.[10][11]

McBride

was later awarded a number of honours including a medal and prize money

by the prestigious L'Institut de la Vie in Paris.[12]

In the United Kingdom the drug was licensed in 1958 and, of the babies

born with defects, 456 survived. The drug was withdrawn in 1961 but it

wasn't until 1968, after a long campaign by The Sunday Times newspaper,

that a compensation settlement for the UK victims was reached with

Distillers Company Limited.[13][14]

In Germany approximately 2,500

[edit]History

[edit]Development

[edit]Birth defects

mean ranges from approximately 5 to 7 hours

following a single dose; not altered with multiple

doses

?

oral

Half life

Excretion

Therapeutic considerations

Pregnancy cat. X(AU) X(US)

Legal status

Routes

• Prescription only

1962 photo of baby born with an

extra appendage connected to the

foot caused by the pregnant mother

● 6 Notable children affected

● 7 References

● 8 Further reading

● 9 External links

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thalidomide babies were born.[11]

The impact in the United States was minimized when the pharmacologist Frances Oldham Kelsey refused Food

and Drug Administration (FDA) approval for an application from Richardson Merrell to market thalidomide,

saying more study was needed. Richardson Merrell gave the tablets to doctors on the understanding that the

drug was still under investigation. Seventeen children in the U.S. were born with the defects.[9]

In 1962, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug

can receive approval for sale in the U.S.[15]

Other countries enacted similar legislation, and thalidomide was

not prescribed or sold for decades.

However, it was soon found that it was only one particular optical isomer of thalidomide which caused

the teratogenicity. The pair of enantiomers, although mirror images of each other, cause different effects[16]

although it is now known that the "safe" isomer can be converted to the teratogenic one in the human body.[11][17]

(see Teratogenic mechanism ).

In 1964 Prof. Jacob Sheskin, Professor at the Hebrew University of Jerusalem at Hadassah University Hospital (he

was also the chief staff and manager of Hansen Leper Hospital in Jerusalem), administered thalidomide to a

critically ill patient with erythema nodosum leprosum (ENL), a painful complication of leprosy, in an attempt to

relieve his pain in spite of the ban. The patient slept for hours, and was able to get out of bed without aid

upon awakening. The result was followed by more favorable experiences and then by a clinical trial. [18]

He found that patients with erythema nodosum leprosum, a painful skin condition, experienced relief of their pain

by taking thalidomide. Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York

City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan partnered

with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown

that thalidomide is effective in the treatment of multiple myeloma, and it was approved for use in the United

States by the FDA for use in this malignancy. The FDA has also since approved the drug's use in the treatment

of erythema nodosum leprosum. There are studies underway to determine the drug's effects on arachnoiditis

and several types of cancers. However, physicians and patients alike must go through a special process to

prescribe and receive thalidomide (S.T.E.P.S) to ensure no more children are born with birth defects traceable to

the medication. Celgene Corporation has also developed analogues to thalidomide, such as lenalidomide, that

are substantially more powerful and have fewer side effects - except for greater myelosuppression.[19]

[edit]Revived interest

taking Thalidomide

1962: FDA inspector Frances

Oldham Kelsey receives an award

from President John F. Kennedy for

blocking sale of Thalidomide in the

United States

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On July 16, 1998, the FDA approved the use of thalidomide for the treatment of lesions associated with

Erythema Nodosum Leprosum (ENL). Because of thalidomide’s potential for causing birth defects, the distribution

of the drug was permitted only under tightly controlled conditions. The FDA required that Celgene Corporation,

which planned to market thalidomide under the brand name Thalomid , establish a System

for Thalidomide Education and Prescribing Safety (S.T.E.P.S) oversight program. The conditions required under

the program include; limiting prescription and dispensing rights only to authorized prescribers and

pharmacies, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about

the risks associated with the drug and providing periodic pregnancy tests for women who are prescribed it.[20]

On May 26, 2006, the U.S. Food and Drug Administration granted accelerated approval for thalidomide

(Thalomid, Celgene Corporation) in combination with dexamethasone for the treatment of newly diagnosed

multiple myeloma (MM) patients.[21]

The FDA approval came seven years after the first reports of efficacy in

the medical literature[22]

and Celgene took advantage of "off-label" marketing opportunities to promote the drug

in advance of its FDA approval for the myeloma indication. Thalomid, as the drug is commercially known, sold

over $300 million per year, while only approved for leprosy.[23]

Thalidomide is available to only a small number of patients in the UK, generally in specialist cancer treatment

centres where research trials are taking place and specialist doctors have experience in its use.[24]

Brazil has the highest prevalence rate of leprosy in the world and thalidomide has been used by Brazilian

physicians as the drug of choice for the treatment of severe ENL since 1965. A study published in 1994 found

61 people born after 1965 whose limb defects and exposure history were compatible with thalidomide

embryopathy. In 63.6% of these cases, thalidomide had been prescribed without the physician informing the

patient about the drug's teratogenicity. Since then production, dispensing and prescription of thalidomide have

been strictly controlled and no cases of thalidomide embryopathy are thought to have occurred since 1997.[25]

Research on thalidomide slowed in the 1960s, but never stopped. At least one university in the United States

pursues thalidomide research, even though performed by only one tenured professor. The medication is an

example of how potentially dangerous compounds can be used therapeutically with appropriate precautions

and procedures.

[edit]United States

[edit]United Kingdom

[edit]Brazil

[edit]Possible indications

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Serious infections including sepsis and tuberculosis cause the level of Tumor necrosis factor-alpha (TNFα) to

rise. TNFα is a chemical mediator in the body, and it may enhance the wasting process in cancer patients as

well. Thalidomide may reduce the levels of TNFα, and it is possible that the drug's effect on ENL is caused by

this mechanism.[15]

Thalidomide also has potent anti-inflammatory effects that may help ENL patients. In July 1998, the FDA

approved the application of Celgene to distribute thalidomide under the brand name Thalomid for treatment of

ENL. Pharmion Corporation, who licensed the rights to market Thalidomide in Europe, Australia and various

other territories from Celgene, received approval for its use against multiple myeloma in Australia and New Zealand

in 2003.[26]

Thalomid, in conjunction with dexamethasone, is now standard therapy for multiple myeloma.

Thalidomide is also prescribed for its anti-inflammatory effects in actinic prurigo, an autoimmune skin disease.

Thalidomide also inhibits the growth of new blood vessels (angiogenesis), which may be useful in treating

macular degeneration and other diseases. This effect helps AIDS patients with Kaposi's sarcoma, although there

are better and cheaper drugs to treat the condition. Thalidomide may be able to fight painful, debilitating

aphthous lesions in the mouth and esophagus of AIDS patients which prevent them from eating. The FDA formed

a Thalidomide Working Group in 1994 to provide consistency between its divisions, with particular emphasis on

safety monitoring. The agency also imposed severe restrictions on the distribution of Thalomid through the System

for Thalidomide Education and Prescribing Safety (STEPS) program.[15]

Thalidomide is also being investigated for treating symptoms of prostate cancer, glioblastoma,

lymphoma, arachnoiditis, Behçet's disease, and Crohn's disease. In a small trial, Australian researchers

found thalidomide sparked a doubling of the number of T cells in patients, allowing the patients' own immune

system to attack cancer cells.

Full list of indications currently being investigated in clinical trials; [27]

● Amyotrophic lateral sclerosis

● Aphthous ulcer

● Behcet's syndrome

● Brain cancer

● Breast cancer

● Cachexia

● Colorectal cancer

● Congestive heart failure

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Thalidomide was first tested as a single agent for the treatment of multiple myeloma in 1999 due to

its antiangiogenesis activity.[28]

Since then many studies have shown that thalidomide in combination

● Crohn's disease

● Diarrhoea

● Fibrodysplasia ossificans progressiva

● Graft-versus-host disease

● Haematological malignancies

● HIV infections

● Hodgkin's disease

● Kaposi's sarcoma

● Leukaemia

● Macular degeneration

● Malignant melanoma

● Mycobacterium avium complex infections

● Myelodysplastic syndromes

● Myelofibrosis

● Myeloid leukaemia

● Non-Hodgkin's lymphoma

● Non-small cell lung cancer

● Ovarian cancer

● Pain

● Prostate cancer

● Prurigo nodularis

● Renal cancer

● Rheumatoid arthritis

● Small cell lung cancer

● Systemic lupus erythematosus

● Thyroid cancer

● Tuberculosis

[edit]Thalidomide and multiple myeloma

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with dexamethasone has increased the survival of multiple myeloma patients. The combination of thalidomide

and dexamethasone, often in combination with melphalan, is now one of the most common regimens for

patients with newly diagnosed multiple myeloma, with an improved response rate of up to 60-70%.[29][30]

However, thalidomide may also cause side effects such as polyneuropathy, fatigue, skin rash, and

venous thromboembolism (VTE), or blood clots, which could lead to stroke or myocardial infarction.[31]

Bennett et

al. have conducted a systematic review of VTE associated with thalidomide in multiple myeloma patients.[32]

They have found that when Thalidomide was administered without prophylaxis, VTE rates reached as high as

26%. Due to the high rates of VTE associated with thalidomide in combination with dexamethasone or doxorubicin,

a black box warning was added in 2006 to the package insert for thalidomide, indicating that patients with

multiple myeloma who receive thalidomide-dexamethasone may benefit from concurrent

thromboembolism prophylaxis or aspirin. In addition, due to these side effects, newer drugs, such as a

thalidomide derivative lenalidomide (marketed as Revlimid) and bortezomib (marketed as Velcade) have increased

in popularity.[citation needed

]

Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. The (R )

enantiomer is effective against morning sickness but the (S ) is teratogenic and causes birth defects.

The enantiomers can interconvert in vivo[33]

– that is, if a human is given pure (R )-

thalidomide or (S )-thalidomide, both isomers can be found in the serum – therefore, administering

only one enantiomer will not prevent the teratogenic effect.

The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the

proposal of fifteen or sixteen plausible mechanisms.[34]

A theoretical synthesis in 2000[34]

suggested

the following mechanism: Thalidomide intercalates (inserts itself) into DNA in G-C (guanine-cytosine)

rich regions.[35][36]

Due to its glutarimide part, (S) thalidomide fits neatly into the major groove of DNA

at purine sites.[34]

Such intercalation impacts upon the promoter regions of the genes controlling the

development of limbs, ears, and eyes such as IGF-I and FGF-2. These normally activate the production of the

cell surface attachment integrin αvβ3 with the resulting alphavbeta3 integrin dimer stimulating angiogenesis

in developing limb buds. This then promotes the outgrowth of the bud (IGF-I and FGF-2 are also both known

to stimulate angiogenesis). Therefore, by inhibiting the chain of events, thalidomide causes the truncation of

limb development. In 2009 this theory[34]

received strong support, with research showing "conclusively that loss

of newly formed blood vessels is the primary cause of thalidomide teratogenesis, and developing limbs are

[37]

[edit]Teratogenic mechanism

The two enantiomers of thalidomide:

Left: (S )-thalidomide

Right: (R )-thalidomide

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particularly susceptible because of their relatively immature, highly angiogenic vessel network."

Apart from its infamous tendency to induce birth defects and peripheral neuropathy, the main side effects

of thalidomide include fatigue and constipation.[citation needed

] It is also associated

with an increased risk of deep vein thrombosis especially when combined with dexamethasone, as it is for

treatment of multiple myeloma.[citation needed

] High doses can lead to

pulmonary oedema, atelectasis, aspiration pneumonia and

refractory hypotension.[citation needed

] In multiple myeloma patients, concomitant

use with zoledronic acid may lead to increased incidence of

renal dysfunction.[citation needed

]

The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study

and creation of thalidomide analogs. In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the

first commercially useful derivative. Revlimid is only available in a restricted distribution setting to avoid its use

during pregnancy. Further studies are conducted to find safer compounds with useful qualities. Another

analog, Actimid (CC-4047), is in the clinical trial phase.[38]

These thalidomide analogs can be used to treat

different diseases, or used in a regimen to fight two conditions.

[edit]Other side effects

[edit]Thalidomide analogs

[edit]Notable children affected

● Mat Fraser, a comedian, actor, co-presenter of the BBC's Ouch Podcast.

● Alison Lapper is an English artist who was the subject of Marc Quinn's sculpture

Alison Lapper Pregnant , which was on display in

Trafalgar Square in London from 2005 until late 2007.

● Alvin Law, a motivational speaker and former radio broadcaster.

● Tony Meléndez is a guitarist who was born without arms. He plays only with his feet.

● Terry Wiles internationally known through On Giants' Shoulders ,

a book and film about his life.

● Brett Nielsen, a musician , was the first Australian thalidomide child.

● Louise Medus Mansell, daughter of David Mason, campaigner for increased compensation for Thalidomide

children, born with no arms or legs.[39]

● Thomas Quasthoff is an internationally acclaimed bass-baritone who describes himself: "1.34 meters tall, short

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[edit]References

arms, seven fingers - four right, three left - large, relatively well formed head, brown eyes, distinctive lips;

profession: singer."[40]

● Matthias Berg is a lawyer, renowned hornist and multiple Paralympics gold medalist.

● Melody Potter Native Alabamian disability activist, severe deformities, no arms or legs.

● Giancarlo Cosio, Italian Waterski World disabled Champion.

● David Lega, Swedish swimmer. Paralympian and current holder of 5 world records. [41]

● Gary Skyner, a comedian and motivational speaker.

● Frankie Shum, an actor, starred in Kung fu films Crippled Masters and Crippled Heroes.

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of thalidomide teratogenicity? Z Naturforsch [C]. 41(11-12):1057-61. PMID 2953123

Thalidomide - Wikipedia, the free encyclopedia

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[edit]Further reading

[edit]External links

● Stephens, Trent; Brynner, Rock (2001-12-24). Dark Remedy:

The Impact of Thalidomide and

Its Revival as a Vital Medicine .

Perseus. ISBN 0-7382-0590-7.

● Knightley, Phillip; Evans, Harold. Potter, Elaine. Wallace, Marjorie. (1979). Suffer

The Children: The Story

of Thalidomide . New York: The Viking Press. ISBN 0-670-68114-8.

● Thalidomide product monograph (Needs registration)

● Multiple Myeloma Research Foundation article on Thalidomide

● International Myeloma Foundation article on Thalidomide

● Thalidomide — Annotated List of Links (covering English and German pages)

● WHO Pharmaceuticals Newsletter No. 2, 2003 - See page 11, Feature Article

● Grünenthal GmbH - Thalidomide

● Celgene website on Thalomid

● The Return of Thalidomide - BBC

36. ^ Huang PH, McBride WG (1997). "Interaction of [glutarimide-2-14C]-thalidomide with rat embryonic DNA in

vivo". Teratogenesis, Carcinogenesis,

and Mutagenesis 17 (1): 1–5. doi:10.1002/(SICI)1520-6866(1997)17:1<1::AID-

TCM2>3.0.CO;2-L. PMID 9249925.

37. ^ Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N (May 2009). "Thalidomide induces limb defects by

preventing angiogenic outgrowth during early limb formation". Proceedings of

the National Academy of Sciences

of the United States of America 106 (21): 8573–

8. doi:10.1073/pnas.0901505106. PMID 19433787.

38. ^ Search of: pomalidomide - ClinicalTrials.gov

39. ^ Courtenay-Smith, Natasha (2008-04-23). "A truly special love story: Two married thalidomide survivors living happily 50

years after drug's launch". London: The Daily Mail. http://www.dailymail.co.uk/news/article-561360/A-truly-special-love-story-

Two-married-thalidomide-survivors-living-happily-50-years-drugs-launch.html. Retrieved 2009-06-18.

40. ^ Orpheus lives: A small good thing in Quastoff Retrieved on 2008-10-22

41. ^ David Lega personal website

Thalidomide - Wikipedia, the free encyclopedia

http://en.wikipedia.org/wiki/Thalidomide (13 of 16) [8/26/2009 4:22:48 PM]

● CBC Digital Archives – Thalidomide: Bitter Pills, Broken Promises

● Thalidomide UK

● The Thalidomide Trust

● "The Big Pitch: How would you conduct a campaign for the new Thalidomide Drugs?", forum of pharmaceutical

and medical marketing professionals commenting on how they would address the Thalidomine controversies.

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